Cardiovascular disease is the number one cause of death in the United States today. High levels of cholesterol and triglycerides have been identified as major contributing factors to heart disease. Furthermore, lipid-lowering drugs such as statins and fibrates have been shown to reduce the incidence of coronary disease. Although current drugs have enjoyed some success in this area, a need remains for improved drugs with fewer side effects. The goal of this proposal is to develop a fluorescent zebrafish assay (Z-Lipotrack) to identify new drugs for lipid management. The zebrafish has many advantages to model vertebrate diseases. In particular, they process lipids through the digestive system in a manner similar to mammals. Because zebrafish larvae are essentially transparent, such processing can be readily observed in the whole organism, with the aid of fluorescent lipid substrates, which are swallowed by the zebrafish larvae and transported from the intestine to the liver and gall bladder. To increase the usefulness of Z-Lipotrack for high throughput drug screening, a fluorescent plate reader will be developed to automatically image the Z-Lipotrack assay. Secondly, the use of Z-Lipotrack for compound optimization will be evaluated. Finally, compounds identified as potential lipid-lowering drugs in Phase 1will be fully characterized and optimized through the use of medicinal chemistry to identify lead compounds for further animal and human studies.